Aminopterin and its N-10-methyl derivative, methotrexate, have long been recognized as powerful antineoplastic agents. Methotrexate has enjoyed some thirty years of acceptance as a clinically useful anti-cancer drug. The drugs are antimetabolites inhibiting dihydrofolate reductase (DHFR). They affect both neoplastic and normal host tissue.
J. I. DeGraw and F. M. Sirotnak, Cancer Treatment Reports, 62, 1047 (1978), British Pat. No. 1,534,238, dated Nov. 29, 1978 and U.S. application Ser. No. 75,913, filed Sept. 17, 1979 report that 10-deazaminopterin exhibited more potent antitumor activity than aminopterin and methotrexate in experimental tumors in mice. Specifically, it was found to have a wider spectrum of activity, better penetration of tumor tissue and more favorable distribution and kinetic parameters for tumor versus normal tissue. The cited U.S. patent application also teaches that antitumor effect and the spectrum of activity of 10-deazaminopterin were enhanced by incorporation of alkyl groups of short chain length at the 10 carbon atom.
Alterations of the pteridine ring of folic acid have also been investigated. The synthesis and antifolate activity of 8-deazafolic acid was reported by J. I. DeGraw, R. L. Kisliuk, Y. Gaumont and C. M. Baugh J Med Che, (1974) 17:470 and 8,10-dideasafolic acid was reported in J. I. Degraw, R. L. Kisliuk, V. H. Brown and Y. Gaumont, Chem Biol Pteridines (1979) 6:229. Both of these compounds were active antifolates, but did not significantly affect DHFR. A. Srinivasan and A. D. Broom, J Org Chem (1981) 46:1777 reported the preparation of 8-deazaminopterin and 8-deazamethotrexate, but did not report biological activity for the compounds.
More recently, it was disclosed that 8,10-dideazaminopterin exhibited biological activity (DeGraw, J. I., et al, J Hetero Chem, (1982) 19:1587. A poster session at the International Symposium on Pteridine and Folic Acid Analogs, Scotland in September 1982 disclosed prepraration of the n-propyl analog. It has now been found that 10-methyl-8,10-dideazaminopterin and 10-ethyl-8,10-didiazaminopterin have surprisingly potent anti-neoplastic activity as compared with the unsubstituted and n-propyl analogs.